Combining familial hypercholesterolemia and statin genetic studies as a strategy for the implementation of pharmacogenomics. A multidisciplinary approach.

The diagnostic process of familial hypercholesterolemia frequently involves the use of genetic studies. Patients are treated with lipid-lowering drugs, frequently statins. Although pharmacogenomic clinical practice guidelines focusing on genotype-based statin prescription have been published, their use in routine clinical practice remains very modest.We have implemented a new NGS strategy that combines a panel of genes related to familial hypercholesterolemia with genomic regions related to the pharmacogenomics of lipid-lowering drugs described in clinical practice guidelines and in EMA and FDA drug labels. A multidisciplinary team of doctors, biologists, and pharmacists creates a clinical report that provides diagnostic and therapeutic findings using a knowledge management and clinical decision support system, as well as an algorithm for treatment selection.For 12 months, a total of 483 genetic diagnostic studies for familial hypercholesterolemia were carried out, of which 221 (45.8%) requested a complementary pharmacogenomic test. Of these 221 patients, 66.5% were carriers of actionable variants in any of the studied pharmacogenomic pathways: 46.6% of patients in one pathway, 19.0% in two pathways, and 0.9% in three pathways. 45.7% of patients could have a response to atorvastatin different from that of the reference population, 45.7% for simvastatin and lovastatin, 29.0% for fluvastatin, and 6.7% patients for pitavastatin.This implementation approach facilitates the incorporation of pharmacogenomic studies in clinical care practice, it does not add complexity nor additional steps to laboratory processes, and improves the pharmacotherapeutic process of patients.

Results of the implementation of a pharmacogenomics platform based on NGS technologies. Combining clinical and research approaches.

OBJECTIVE: As more genes are incorporated into pharmacogenomic care  processes and more importance is given to rare variants, the use of targeted  capture sequencing panels has been proposed as a very efficient alternative  due to their affordability, high throughput, and deep coverage, all of them  characteristics of high-quality next-generation sequencing data. The purpose of  this study is to describe the prevalence of clinically actionable  pharmacogenetic variants previously described in the scientific literature, as  well as that of new variants identified by next-generation sequencing  technologies, and to evaluate the drugs potentially affected by such variants. METHOD: A panel of 18 clinically actionable pharmacogenomics-related genes  was evaluated in 41 subjects diagnosed with breast cancer undergoing  neoadjuvant treatment. The prevalence of previously descri- bed clinically  actionable variants as well as of phenotypes classified according to current  interpretation standards was studied. The pharmacological treatments  potentially affected by the identified variants were also evaluated. An  estimation was made of the prevalence of not previously described, possibly  deleterious, variants selected using bioinformatics criteria. RESULTS: All subjects carried clinically actionable variants, with a mean of 4.02  genes affected by each variant per individual. VKORC1, CYP4F2, CYP2C19,  CYP2D6 and CYP2B6 were the most polymorphic genes and were present with  actionable phenotypes in more than 50% of patients; 15-50% had actionable  phonotypes in UGT1A1, SLCO1B1, CYP2C9 and TPMT and 2-15% in HLA-B,  CYP3A5, HLA-A and DPYD. No actionable variants were identified in RYR1,  CACNA1S, G6PD, F5 and NUDT15. These variants had the potential to affect  response to 84% of the drugs described in the leading pharmacogenetic  guidelines. Possibly deleterious variants not previously described accounted for  11.4% of all clinically actionable variants and were present in 12.2% of  patients. CONCLUSIONS: The results obtained show a high prevalence of clinically actionable variants, both common, i.e., previously described in the  literature, and rare, i.e., not previously studied with conventional technological  approaches. The latter are candidates for a more exhaustive  molecular and/or clinical characterization.

OBJETIVO: A medida que se incorporan más genes a los procesos  farmacogenómicos asistenciales y se otorga más importancia a las variantes raras, el uso de paneles de secuenciación dirigida por captura se ha  propuesto como una alternativa muy eficiente atendiendo a sus costes, su  rendimiento y la cobertura profunda, característica de los datos de  secuenciación de nueva generación de alta calidad. El objeto de este trabajo es  describir la prevalencia de variantes farmacogenéticas clínicamente  procesables descritas previamente en la literatura científica, así como de  nuevas variantes identificadas mediante tecnologías de secuenciación de nueva  generación y evaluar los fármacos potencialmente afectados por estas  variantes.Método: Se evaluó un panel de 18 genes relacionados con la  farmacogenómica clínicamente procesables en 41 individuos con diagnóstico de  cáncer de mama que van a recibir tratamiento adyuvante y neoadyuvante.  Se estudió  la literatura científica, así como de los fenotipos farmacogenéticos  clasificados según los estándares de interpretación actuales. Asimismo, se  evaluaron los tratamientos farmacológicos potencialmente afectados por las  variantes identificadas. Se estimó la prevalencia de variantes posiblemente  deletéreas no descritas previamente seleccionadas con criterios  bioinformáticos. RESULTADOS: Todos los individuos fueron portadores de variantes clínicamente procesables, con una media de 4,02 genes afectados por alguna variante por individuo. Los genes VKORC1, CYP4F2, CYP2C19, CYP2D6 y CYP2B6 fueron los más polimórficos, con más de un 50% de  pacientes con fenotipos procesables; un 15-50% en UGT1A1, SLCO1B1,  CYP2C9 y TPMT y un 2-15% HLA-B, CYP3A5, HLA-A y DPYD. No se  identificaron variantes procesables en RYR1, CACNA1S, G6PD, F5 y NUDT15.  Estas variantes afectarían a la respuesta de un 84% de los fármacos descritos  en las principales guías de farmacogenética. Las variantes posiblemente  deletéreas no descritas previamente supusieron un 11,4% del total de  variantes clínicamente procesables y están presentes en un 12,2% de los  pacientes. CONCLUSIONES: Los resultados obtenidos constatan una alta prevalencia de  variantes clínicamente procesables tanto comunes, previamente descritas en la  literatura, como raras, no estudiadas con abordajes tecnológicos convencionales y candidatas a una caracterización molecular y/o  clínica más exhaustiva.

Development and validation of a next-generation sequencing panel for clinical pharmacogenetics.

The rapid clinical implementation of next generation sequencing techniques is  due to its ability to sequence a large number of genetic regions at lower costs  than conventional techniques. However, its use in the field of pharmacogenetics  is still very limited. OBJECTIVE: Design, development, implementation and validation of a clinical  pharmacogenetics next-generation sequencing panel. METHOD: We developed a panel of hybrid capture probes (SureSelect®) for the  analysis of the genetic regions of clinical interest collected by literature search  and using Illumina HiSeq 1500® sequencing platform. We developed a  bioinformatic algorithm for variant annotation, haplotype inference and  determination of structural variants in the genes of interest. The results obtained were validated with Coriell® reference material from the pharmacogenetic  repositories. RESULTS: The developed panel allows the study of a total of 12,794 regions comprised in 389 genes. Validation results showed a sensitivity greater  than 99% for single nucleotide variants and small INDELs. Haplotype imputation was consistent with the consensus results in the characterized  reference materials. Furthermore, the developed tool was able to correctly  identify different types of CYP2D6 copy number variations as well as a wide  variety of HLA-B alleles. CONCLUSIONS: This technology represents an appropriate alternative for its  clinical use with advantages over conventional techniques in its throughput and  complex gene study capabilities (CYP2D6, HLA-B).

La rápida implantación clínica de las técnicas de secuenciación masiva en  paralelo se debe a su capacidad para secuenciar un gran número de regiones  genéticas con un coste menor a las técnicas convencionales. Sin embargo, su  uso en el ámbito de la farmacogenética es, todavía, muy escaso.Objetivo: Diseño, desarrollo, implementación y validación de un panel de  secuenciación masiva en paralelo de farmacogenética orientado a la práctica  clínica.Método: Se desarrolló un panel de sondas de captura híbrida (SureSelect ®)  para el análisis de las regiones genéticas de interés clínico recopiladas mediante  búsqueda bibliográfica. Se empleó la plataforma de secuenciación Illumina HiSeq 1500®. Se desarrolló un algoritmo de análisis bioinformático para la anotación  de variantes puntuales, inferencia de haplotipos y determinación de variantes  estructurales en los genes de interés. Los resultados obtenidos se validaron con  materiales de referencia Coriell® de los repositorios de farmacogenética.Resultados: El panel desarrollado permite el estudio de un total de 12.794  regiones comprendidas en 389 genes. Los resultados de validación mostraron  una sensibilidad superior al 99% para variantes puntuales e inserciones y  deleciones pequeñas. La imputación de haplotipos fue coherente con los  resultados consenso de los materiales de referencia caracterizados. Además, la  herramienta desarrollada pudo identificar correctamente diferentes tipos de  variaciones de número de copias de CYP2D6, así como una gran variedad de  alelos de HLA-B.Conclusiones: Esta tecnología representa una alternativa adecuada para su  empleo asistencial con ventajas frente a las técnicas convencionales en su  rendimiento de producción y sus capacidades de estudio de genes complejos  (CYP2D6, HLA-B).

Coronary vascular disease event risk and metabolic syndrome prevalence in patients enrolled in an assertive treatment community program.

OBJECTIVE: To examine the risk of coronary vascular disease event (CVDE) and the prevalence metabolic syndrome (MS) and its cardiovascular risk factors (CVRF) in patients with severe mental illnesses enrolled in an assertive treatment community program (ATC) in Spain. METHOD: We carried out a cross-sectional descriptive study with all of the patients included in an ATC program in 2016 in a health area with 547,328 inhabitants in Galicia, Spain. We identified the CVRF in all the individuals, and calculated MS and 10-year CVDE. We also compared the prevalence of all traits in our cohort and the general population. RESULTS: The 10-year median of coronary vascular disease event (CVDE10) was 8.4%. The percentage of individuals with high CVDE10 (>5%) was 41.2% The CVDE10 median was higher in men than women (10.5% vs 5.1%, p<0.001). MS was detected in 50% of patients without differences between men and women (51.2% vs 48.2%). A prevalence of 68% was found for smoking, 55% for dyslipidemia, 47% for obesity, 29% for impaired glucose metabolism, and 38% for hypertension. Women showed a higher prevalence of obesity measured by elevated waist circumference (88.9% vs 55.6%, p=0.003). Men showed a higher prevalence of arterial hypertension (46.6% vs 22.2%, p=0.0001). CONCLUSIONS: The SMD Patients enrolled in ATC programs had a 1.5-times higher prevalence of MS and 8 times higher CVDE10 than those reported in the general population. Individual CVRF were also higher in the SMD patients. Prevention, early detection, and comprehensive treatment are important issues for patients with severe mental illnesses.

Study of cases of abiraterone discontinuation due to toxicity in pre-chemotherapy after 1 year's experience.

Abiraterone acetate is a potent and irreversible inhibitor of cytochrome p450 17A1 that suppresses androgen synthesis. It is approved for chemotherapy-naive and docetaxel-treated patients with metastatic castration-resistant prostate cancer. We describe the protocol for use of abiraterone in metastatic castration-resistant prostate cancer chemotherapy naive patients has been implanted in our centre and we review the cases of those patients whose adverse effects have forced the discontinuation of treatment. The side effects fit the safety profile of abiraterone, speed of their appearance and severity indicate that you should perform a thorough follow-up of these patients especially in the early phases of treatment.